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      PD-1 Blockade in Tumors with Mismatch-Repair Deficiency

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      New England Journal of Medicine
      Massachusetts Medical Society

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          Abstract

          Somatic mutations have the potential to encode "non-self" immunogenic antigens. We hypothesized that tumors with a large number of somatic mutations due to mismatch-repair defects may be susceptible to immune checkpoint blockade.

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          Incidence and functional consequences of hMLH1 promoter hypermethylation in colorectal carcinoma.

          Inactivation of the genes involved in DNA mismatch repair is associated with microsatellite instability (MSI) in colorectal cancer. We report that hypermethylation of the 5' CpG island of hMLH1 is found in the majority of sporadic primary colorectal cancers with MSI, and that this methylation was often, but not invariably, associated with loss of hMLH1 protein expression. Such methylation also occurred, but was less common, in MSI- tumors, as well as in MSI+ tumors with known mutations of a mismatch repair gene (MMR). No hypermethylation of hMSH2 was found. Hypermethylation of colorectal cancer cell lines with MSI also was frequently observed, and in such cases, reversal of the methylation with 5-aza-2'-deoxycytidine not only resulted in reexpression of hMLH1 protein, but also in restoration of the MMR capacity in MMR-deficient cell lines. Our results suggest that microsatellite instability in sporadic colorectal cancer often results from epigenetic inactivation of hMLH1 in association with DNA methylation.
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            Author and article information

            Journal
            New England Journal of Medicine
            N Engl J Med
            Massachusetts Medical Society
            0028-4793
            1533-4406
            June 25 2015
            June 25 2015
            : 372
            : 26
            : 2509-2520
            Affiliations
            [1 ]From the Swim Across America Laboratory (D.T.L., J.N.U., B.R.B., L.A.D.), Sidney Kimmel Comprehensive Cancer Center (D.T.L., J.N.U., H.W., H.K., A.D.E., A.D.S., B.S.L., N.S.A., D.L., B.B., R.C.D., D.M.P., N.P., K.W.K., S.Z., B.V., L.A.D.), Ludwig Center and Howard Hughes Medical Institute (B.R.B., A.D.S., N.P., K.W.K., S.Z., B.V., L.A.D.), and the Departments of Radiology (A.Z.) and Pathology (F.B., T.H., R.H.H., L.D.W., N.C., T.C.C., J.M.T., R.A.A., J.R.E.), Johns Hopkins University School of Medicine,...
            Article
            10.1056/NEJMoa1500596
            4481136
            26028255
            28b9307c-13cf-411a-b6ad-e183242af6a1
            © 2015
            History

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